Leptin Signaling in Hypothalamic Neurons and Glutamate Receptors

下丘脑神经元和谷氨酸受体中的瘦素信号传导

• 批准号: 8661767
• 负责人: YOUNG-BUM KIM
• 金额: $ 37.28万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-19 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661767
• 关键词: Acute; Affect; Body Weight; Brain; C-terminal; Cell Line; Data; Dendrites; Desire for food; Development; Eating; Energy Intake; Fatty acid glycerol esters; Future; Glutamate Receptor; Glutamates; Hormones; Human; Hypothalamic structure; In Vitro; Injection of therapeutic agent; Laboratories; Lead; Leptin; Leptin deficiency; Mediating; Methodology; Morphology; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neurobiology; Neuronal Plasticity; Neurons; Obesity; Pathway interactions; Phosphorylation; Play; Receptor Signaling; Regulation; Rodent; Role; Signal Pathway; Signal Transduction; Slice; Structure; Synapses; Testing; Tyrosine; Tyrosine Phosphorylation; density; energy balance; feeding; in vivo; leptin receptor; mind control; neuronal excitability; novel; receptor; response; synaptogenesis

DESCRIPTION (provided by applicant): The fat-derived hormone leptin acts on neurons in the hypothalamus to regulate food intake and body weight in rodents and humans. The aim of this proposal is to identify and characterize a novel signaling mechanism whereby leptin affects neuronal activity of POMC and AgRP neurons. Specifically, we will test the hypothesis that leptin receptors localized on dendrites of POMC and AGRP neurons regulates phosphorylation and activity of post-synaptic glutamate receptors (NMDA-R(NR1/NR2B)), and that this pathway influences dendrite morphology, and eventually plays a role in energy balance regulation in mice. To achieve this, we will investigate leptin receptor signaling and action in cell lines, primary neuronal cultures, brain slices and in vivo in mice. We will use state- of-the art methodologies and create/use novel genetically modified mice, and study leptin's effects on neuronal plasticity and on energy balance in mice lacking specific NMDA receptor subunits in POMC or AgRP neurons. Findings from this proposal will lead to a significant advancement in our understanding of leptin receptor neurobiology. We will elucidate a new CNS pathway whereby leptin regulates energy balance.

描述（由申请人提供）：脂肪源性激素瘦素作用于下丘脑的神经元，调节啮齿类动物和人类的食物摄入量和体重。该提案的目的是确定和表征瘦素影响 POMC 和 AgRP 神经元的神经元活动的新信号传导机制。具体来说，我们将测试以下假设：位于 POMC 和 AGRP 神经元树突上的瘦素受体调节突触后谷氨酸受体 (NMDA-R(NR1/NR2B)) 的磷酸化和活性，并且该途径影响树突形态，并最终发挥作用在小鼠能量平衡调节中发挥作用。为了实现这一目标，我们将研究细胞系、原代神经元培养物、脑切片和小鼠体内的瘦素受体信号传导和作用。我们将使用最先进的方法并创建/使用新型转基因小鼠，并研究瘦素对 POMC 或 AgRP 神经元中缺乏特定 NMDA 受体亚基的小鼠的神经元可塑性和能量平衡的影响。该提案的发现将极大地促进我们对瘦素受体神经生物学的理解。我们将阐明瘦素调节能量平衡的新中枢神经系统途径。